SOLID ORGAN TRANSPLANTATION INFECTONS

SOLID ORGAN TRANSPLANTATION INFECTONS

Worldwide, an estimated 119,873 solid organ transplants were performed in 2014. In the United States, 30,970 organ transplantations were performed in 2015. Renal transplants were the most common, followed by those of the liver, heart, lung, and others, including dual organ, pancreatic, and intestinal transplantation. Over the last several decades, the field of solid organ transplantation (SOT) science and practice has advanced significantly, only to be continually challenged by the risks for infection in SOT recipients.

The positive effects of the immunosuppressive agents, obligatory for the prevention of organ rejection, have been tempered by the negative effects of these same therapies, leading to various infections that range in both frequency and severity. Fortunately, experienced SOT researchers and practitioners have been involved in the development and implementation of proactive guidelines such as the 2006 American Society of Transplantation guidelines  on screening, monitoring, and reporting of infectious complications in SOT recipients.

Newer immunomodulating agents have been developed, increasing the number of therapies that prevent organ rejection. However, this has simultaneously created newer unwanted opportunities for pathogens to cause infectious complications.  These adverse effects are the result of their negative impact on both the cellular and humoral arms of the SOT recipient's immune system. Fortunately, newer diagnostic laboratory methods have also added much-needed capacity to identify the presence and types of pathogens, often early enough in the SOT recipient’s course to prevent or mitigate severe infection. 

Immunosuppressive agents used in transplantation target either single or multiple sites in the immune system, thus markedly enhancing their effect in prevention or treatment of organ rejection (via either single-drug or combination regimens). Therefore, these drugs represent a dual-edged sword, potentially predisposing solid organ transplantation (SOT) recipients to all categories of pathogens by impairing host defenses.

All of the major determinants of immune competence (host anatomic barriers, mechanisms in innate immunity, acquired capacities, presence or absence of immunomodulating co-infections, and underlying comorbid conditions) may be breached and may result in opportunistic pathogens, causing illness in SOT recipients. Examples of these factors include the following:

  • Immunosuppressive drug–induced antiproliferative activity leading to mucosal erosions
  • Transient cytopenias
  • Uremia
  • Hyperglycemia
  • Malnutrition
  • Use of invasive devices (leading to trauma, colonization, and infection)
  • Abnormalities in tissue perfusion (vascular or surgery-related etiologies)
  • Abscesses
  • Cytomegalovirus (CMV) infection
  • Epstein-Barr virus (EBV) infection
  • HIV infection

Given the complexity of variables that may positively or negatively affect immunosuppression in the SOT recipient, clear attribution of a particular pattern of immunosuppression to a specific immunosuppressive agent or regimen is difficult. Additionally, specific trends in the usage of various immunosuppressive therapies make it difficult to epidemiologically associate certain drugs with specific immunosuppression-related infections. Judgments on the likelihood of infection risks associated with specific drugs can often only be rendered based on minimal or suboptimal data on the infectious complications in immunosuppression drug trials. SOT recipients, like other immunocompromised hosts, often present with a mixture of immunological impairments, including neutropenia and lymphopenia, functional T-cell defects, lack of humoral antibody responses, and tissue damage. All of these add to the overall immunosuppression and predispose to infection with various pathogens.

Steroids

Corticosteroids and glucocorticoids constitute a major component of immunosuppressive medications used in SOT, often considered first-line therapy for allograft rejection. Agents such as prednisone or prednisolone have a myriad of negative effects on the immune system, including cell-mediated immunity impairment (through inhibition of several cytokines, including interleukin [IL]-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and tumor necrosis factor [TNF]), often resulting in T-cell proliferation. Antigen presentation, through reduced expression of major histocompatibility complex molecules, also occurs. Humoral immunity is also suppressed, leading to the diminished production of IL-2 and related receptors, as well as B-cell clone expansion and decreased antibody synthesis.

Steroids induce a widespread decrease in the host inflammatory response, resulting in lipocortin-1 synthesis that can eventually impair migration of cells, phagocytosis, respiratory burst mechanisms, and the release of inflammatory chemokines and cytokines from white blood cells. Finally, apoptotic effects result in cytotoxicity. Clinically, these mechanisms of immunosuppression lead to an increased risk of bacterial, mycobacterial, viral, and fungal infections. Since 2000, steroid use appears to have decreased overall.

Other immunosuppressive agents

In addition to steroids, the following classes of immunosuppressive agents are of clinical significance:

  • Small-molecule drugs, including antiproliferative drugs (eg, azathioprine, mycophenolate mofetil, mycophenolate sodium)
  • Calcineurin inhibitors (eg, cyclosporine, tacrolimus)
  • Inhibitors of mammalian target of rapamycin (mTOR) (eg, sirolimus, everolimus)
  • Protein drugs (polyclonal antilymphocyte antibodies and monoclonal antibodies)

Examples of polyclonal antibodies (targeted against lymphocytes) include antilymphocyte globulin (ALG) and antithymocyte globulin (ATG). Examples of monoclonal antibodies include muromonab-CD3 and basiliximab.

Bacterial infections

Among bacterial pathogens, infection with antibiotic-resistant bacteria that include MRSA, vancomycin-resistant enterococci, and Clostridium difficile, along with gram-negative healthcare-associated bacteria, play a significant role, especially in the postoperative period (<30 days posttransplant). For example, studies have shown that SOT recipients are at higher risk of multidrug-resistant Pseudomonas aeruginosa bloodstream infection, which carries a high mortality rate.

Conversely, although some studies have shown no difference in the severity of C difficile–associated diarrhea (CDAD) in SOT recipients compared with non-SOT recipients, exposure to steroids placed SOT recipients at a significantly higher risk of relapse, often requiring a longer course of CDAD therapy. A 2012 study, which defined complicated clostridium difficile colitis (CCDC) as CDAD associated with graft loss, total colectomy, or death,showed the peak frequency of CDAD to be between 6 and 10 days posttransplantation. Independent risk factors for CDAD included age greater than 55, induction with antithymocyte globulin, and transplant other than kidney alone (liver, heart, pancreas, or combined kidney organ). Predictors of CCDC were white blood cell count >25,000/µL and evidence of pancolitis on computed tomography scan. Colectomy was done with excellent survival (83%) in some patients. 

Opportunistic pathogens such as Legionella remain a major challenge in SOT recipients. Microaspiration of water or inhalation of aerosols contaminated with Legionella can result in outbreaks in transplant centers similar to other healthcare settings. The 2- to 6-month period following SOT is the critical time when these infections are generally seen, although community-acquired Legionella infection can occur any time.

A particularly challenging pathogen is M tuberculosis.  Most tuberculosis-related illnesses in the SOT recipient are caused by reactivation of tuberculosis in the recipient in the context of transplantation-related immunosuppression.  Only approximately 4% of tuberculous infections in recipients are donor-transmitted. 

Data from European centers indicate a 9.5% attributable mortality rate in SOT recipients who develop clinical tuberculosis, with age and lung transplantation being independent risk factors.  Particularly important issues include (1) the higher prevalence of atypical presentations, including extrapulmonary tuberculosis and disseminated disease among SOT recipients; (2) the critical need to identify and treat latent tuberculosis; and (3) management of pharmacological toxicity and drug interactions between tuberculosis therapies and SOT-related medications. Drug-resistant tuberculosis can be particularly important in SOT recipients, given the challenges of such disease in an immunocompromised host. 

The association between Helicobacter pylori and gastrointestinal disease (eg, peptic ulcer disease, chronic gastritis, gastric adenocarcinoma, mucosa-associated lymphatic tissue lymphoma) is well known. The prevalence of H pylori appears to be similar between SOT and nontransplant patients but tends to decrease after transplantation, likely because of the significant impact of post-SOT antimicrobial therapy.  The incidence of H pylori –related complications does not appear to increase in the post-SOT phase; however post-SOT management should still include surveillance and monitoring for these complications and prompt preemptive interventions for H pylori.

Viral infections

Many viruses associated with SOT lead to opportunistic illness. These include CMV, EBV (and PTLD), and BK virus, as well as viruses previously considered less significant in SOT, such as hepatitis E.  Emerging pathogens such as arenaviruses are associated with fatalities. 

CMV is the most important viral pathogen to consider in SOT recipients. More than half of SOT recipients develop CMV infection within the first 3 months after transplantation; however, like other pathogens, CMV can also cause illness in later phases.  The general prevalence of CMV seropositivity is 80%-90%, with most primary infections occurring in childhood or adolescence. Latent infection reservoirs include the reticuloendothelial system, peripheral lymphocytes, and monocytes, resulting in later reactivation in the context of immunosuppressive therapies. Well-designed studies have shown that patients treated with sirolimus have a lower incidence of CMV infection. Those patients likely received induction therapy with T-cell depletion. 

However, CMV infection can result from allograft infection, blood products, or natural infection posttransplantation among CMV-negative SOT recipients. Besides nonspecific febrile presentations, CMV can result in invasive disease and organ dysfunction.

Of note, it is still unclear why CMV does not usually present with retinitis syndromes in SOT recipients, unlike in individuals with advanced HIV/AIDS in whom cellular immune dysfunction is also very prevalent. Copathogens, including HHV-6 or HHV-7 viruses and P jiroveci, may lead to complicated severe disease patterns. CMV, because of its immunomodulatory effects, may compound existing immunosuppression, causing secondary infections with bacteria and fungi. Prompt and effective management of chronic rejection associated with CMV infection needs to be a priority.

EBV infection is also extremely prevalent, with almost 95% of the population being infected (often asymptomatically) by adulthood. Notwithstanding the common infectious mononucleosis syndrome, it was noted decades ago that EBV can be cultured from Burkitt lymphoma cells. EBV can remain latent in B cells and chronically replicate in oropharyngeal tissue.

Chronic infection with hepatitis E virus, an RNA virus similar to the Caliciviridae family (which includes norovirus), may occur in SOT recipients.  Hepatitis E virus is transmitted via the oral-fecal route and is known to primarily cause acute hepatitis, often with a fulminating course in certain hosts such as third-trimester pregnant women. In industrialized countries, hepatitis E virus tends to have a zoonotic pattern, with pigs, cattle, sheep, ducks, goats, and rats known to be infected. 

SOT recipients with liver, kidney, and kidney-pancreas transplants can develop chronic hepatitis E infection, and viral RNA levels can persist for a median of 15 months after the acute phase of illness is over. Histologic findings in patients with chronic hepatitis C infection have included lymphocytic portal infiltrates with piecemeal necrosis.  SOT recipients with chronic hepatitis E infection were noted to have lower total lymphocyte counts, as well as specific T-cell subsets, including CD2, CD3, and CD4. Seroconversion of hepatitis E virus occurred later in SOT recipients with chronic hepatitis than those whose acute infections resolved.

Fungal infections

Among fungal pathogens, the most common opportunistic fungi include Candidaspecies, molds such as Aspergillus, and cryptococci. [87, 88, 89, 90] Endemic geographically limited systemic mycoses, including coccidioidomycosis, blastomycosis, and histoplasmosis, can cause significant illness in the SOT recipient. [91] Endemic fungal infections may manifest as primary rapidly progressive syndromes with hematogenous dissemination to various organs; in recipients, reactivation infection followed by further spread and re-infection in the context of transplant-related immunosuppression may also occur.

Emerging pathogens, such as FusariumScedosporium, and Trichosporon species, can cause various syndromes  that are similar to those caused by Aspergillusspecies, which also have a vascular predilection, causing invasive disease complicated by hemorrhage and infarction.  Many patients already have metastatic site involvement at the time of presentation, which is associated with high mortality rates—often up to 50% despite intravenous therapy. 

Candida species, the most common fungal pathogens, are associated with a range of presentations, including milder albeit painful forms such as thrush, mucositis, and asymptomatic candiduria. Severe disease with organ involvement is also possible, with manifestations such as hepatosplenic candidiasis, endocarditis, and genitourinary syndromes. Candidal infection presenting as bloodstream infection may also be associated with healthcare settings, especially with the use of invasive devices.

Modified approach to diagnosis of infection in solid organ transplant recipients with fever

This section describes the recommended initial diagnostic evaluation in patients with various syndromes. 

The recommended initial diagnostic evaluation for fever without localizing findings is as follows:

  • Urinalysis and urine culture
  • Chest radiography
  • Blood cultures
  • CMV PCR
  • Purified protein derivative (PPD) (Consider QuantiFERON testing using interferon gamma assays.)
  • Antigen detection tests available for adenovirus, influenza A, respiratory syncytial virus, and rotavirus; PCR may also be available

The recommended initial diagnostic evaluation for pulmonary infiltrates (alveolar pattern) is as follows:

  • PPD (consider QuantiFERON testing using interferon gamma assays)
  • Blood cultures
  • Sputum Gram stain and culture
  • Urine Legionellaand pneumococcal antigens
  • Sputum acid-fast bacillus (AFB) smear and culture (DNA probes if available)
  • Urine Histoplasmaantigen [98] in endemic areas or suggestive travel
  • Bronchoscopy if fever and infiltrates persist

The recommended initial diagnostic evaluation for pulmonary infiltrates (interstitial pattern) is as follows:

  • Workup for pulmonary infiltrates (alveolar pattern) plus CMV PCR
  • Coccidioidesserology, if warranted
  • Bronchoscopy with transbronchial biopsy if fever and infiltrates persist
  • Bronchoalveolar lavage (BAL) fluid for bacterial, viral, fungal,and AFB stains and cultures; direct fluorescent antibody (DFA) and culture forLegionella; DFA for P jiroveci; CMV PCR; cytology; modified AFB smear and culture to identify Nocardia

The recommended initial diagnostic evaluation for diarrhea is as follows:

  • Stool for WBC and cultures (for enteric [ Salmonella, Shigella, Campylobacter)
  • At least 2 separate stool specimens for C difficiletesting (enzyme immunoassay [EIA] acceptable)
  • Three separate stool specimens for ova and parasites
  • CMV PCR (blood)
  • If stool studies unrevealing and diarrhea persists, endoscopic evaluation warranted (with mucosal biopsy); immunohistochemical staining for CMV should be performed

The recommended initial diagnostic evaluation for lymphadenopathy is as follows:

  • EBV PCR, CMV PCR (blood)
  • Bartonella(catscratch disease) serology
  • T gondiiserology
  • PPD (consider QuantiFERON testing using interferon gamma assays)
  • Biopsy of involved lymph node is often diagnostic and performed quickly to exclude PTLD and occult infections (eg, tuberculosis); node tissue should be submitted for histologic examination to look for atypical cells, granulomata, and cultures (aerobic, anaerobic, AFB, fungal and modified AFB)
  • CT scanning of neck, chest, abdomen, and pelvis might be useful to demonstrate the extent of nodal involvement.

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